Héctor Herranz1, Ruifen Weng1 and Stephen M. Cohen1,2
1 - Institute of Molecular and Cell Biology, 61 Biopolis Drive, Singapore 138673, Singapore
2 - Department of Biological Sciences, National University of Singapore, 14 Science Drive 4, Singapore 117543, Singapore
Published in Current Biology on 7th July 2014.
Background: Cancers develop in a complex mutational landscape. Interaction of genetically abnormal cancer cells with normal stromal cells can modify the local microenvironment to promote disease progression, for some tumor types. Genetic models of tumorigenesis provide the opportunity to explore how combinations of cancer driver mutations confer distinct properties on tumors. Previous Drosophila models of EGFR-driven cancer have focused on epithelial neoplasia.
Results: Here, we report a Drosophila genetic model of EGFR-driven tumorigenesis in which the neoplastic transformation depends on interaction between epithelial and mesenchymal cells. We provide evidence that the secreted proteoglycan Perlecan can act as a context-dependent oncogene cooperating with EGFR to promote tumorigenesis. Co-expression of Perlecan in the EGFR expressing epithelial cells potentiates endogenous Wg/Wnt and Dpp/BMP signals from the epithelial cells to support expansion of a mesenchymal compartment. Wg activity is required in the epithelial compartment, while Dpp activity is required in the mesenchymal compartment. This genetically normal mesenchymal compartment is required to support growth and neoplastic transformation of the genetically modified epithelial population.
Conclusions: We report a genetic model of tumor formation that depends on crosstalk between a genetically modified epithelial cell population and normal host mesenchymal cells. Tumorigenesis in this model co-opts a regulatory mechanism that is normally involved in controlling growth of the imaginal disc during development.
Figure Legend: Wg and Dpp Cooperate with EGFR in Tumor Formation
(J) Schematic representation of the crosstalk between the epithelial and mesenchymal cell populations in tumor formation. Wild-type: EGFR, Wg, and Dpp signaling are required to support proliferation of the disc epithelial cells. Dpp produced by the epithelial cells is also required to support the mesenchymal population. EGFR-psq tumor: increased EGFR activity leads to increased production of Wg and Dpp. Wg signaling is required within the epithelial cells. Dpp is no longer required in the epithelial cells, but elevated signaling enhances growth of the mesenchymal population. Under normal circumstances, this leads to hyperplasia. Depletion of pipsqueak (psq) leads to increased expression of the secreted HSPG, Perlecan (Pcn). Pcn potentiates Dpp activity in the mesenchymal population, presumably by increasing capture of Dpp by the mesenchymal cells. An as-yet-unidentified signal (growth factor), which feeds back to promote proliferation of the epithelial cells, is produced by the mesenchymal cells. This combination of signaling activities leads to neoplasia
Confocal micrographs of third instar wing discs of the following genotypes:
(A) apG4:UAS-EGFR, UAS-GFP.
(B) apG4:UAS-EGFR, UAS-wg.
(C) apG4:UAS-EGFR, UAS-dpp.
(D and E) apG4:UAS-EGFR, UAS-wg, UAS-dpp.
(F) apG4:UAS-EGFR, UAS-psqRNAi, UAS-GFP.
(G) apG4:UAS-EGFR, UAS-psqRNAi, UAS-tcf DN.
(H) apG4:UAS-EGFR, UAS-psqRNAi, UAS-MadRNAi.
(I) apG4:UAS-EGFR, UAS-psqRNAi; 15B03-lexA:lexAop-MadRNAi.
GFP is shown in green in (A) and (C)–(F). EGFR is shown in green in (B) and (I). Cut is shown in red in (E). DNA is shown in blue in (A)–(D) and (F)–(I).
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